Abstract

The prophylactic antimalarial activity of atovaquone was determined in a randomized, double-blind, placebo-controlled study of healthy volunteers who were challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi. Subjects were randomly assigned to one of three groups: six received seven daily doses of 750 mg of atovaquone, starting the day before challenge; six received a single dose of 250 mg of atovaquone the day before challenge; and four received placebo. Polymerase chain reaction- and culture-confirmed parasitemia developed in all four placebo recipients, but in none of the drug recipients, indicating that either of the atovaquone regimens provides effective prophylaxis (P = 0.005). However, in low-dose recipients, the drug levels by day 6.5 were profoundly subtherapeutic, indicating that parasites were eliminated prior to the establishment of erythrocytic infection. Atovaquone thus protects non-immune subjects against mosquito-transmitted falciparum malaria, and has causal prophylactic activity.